The prevalence of HIV-associated neurocognitive disorders (HAND) is near 50% despite the widespread use of combined antiretroviral therapy (cART). HAND is a clinical diagnosis based on neurocognitive impairments ranging in severity from mild neurocognitive deficits to a debilitating dementia. HAND is the result of a chronic neuroinflammatory state fueled by host immune activation; however, the key pathophysiological pathways involved remain unclear. In recent years, a small number of host genetic susceptibility loci have been identified that increase risk for HAND or influence its course, suggesting that perturbation of the physiological pathways their gene products are involved in modifies HAND pathogenesis. However, all studies of HAND-related genetic susceptibility loci have relied solely on clinical outcomes; nothing is known of what pathophysiological changes these genetic variants cause. An innovative approach for determining the pathophysiological mechanisms through which genetic susceptibility loci influence HAND is to examine their influence on neuropathological intermediate phenotypes, or NIPs. At its most basic level, HAND is believed to be the end result of a sequence of physiological events that commences with HIV-induced cellular changes that are modified by genetic factors. In the context of the present study, we deem quantifiable neuropathological changes that occur proximal to the beginning of this causal chain of HAND pathogenesis as the NIPs necessary for the behavioral impairments characteristic of HAND. There exist a number of candidate NIPs that are associated with HAND, including synaptodendritic simplification; macrophage infiltration; microglial and astrocyte activation, and beta-amyloid deposition. Through examining the relationship between genetic susceptibility loci and NIPs in brain tissue derived from a clinically well-characterized cohort, it will be possible t determine 1) which genetic variants are biologically relevant to HAND, 2) the pathophysiological mechanisms through which they exert their effect on the neurobehavioral phenotypes, and 3) the relative importance of NIPs as underlying causative factors of HAND. This study is highly relevant to the mission of NIH to elucidate the physiological mechanisms leading to HAND. To accomplish our aims, we will use immunohistochemistry and high throughput quantification procedures to characterize NIPs across multiple brain regions. Our aim is to determine the extent to which genotype and important co-factors (e.g., age, substance use, cART use) modify these NIPs. Our second aim will determine the linear causative relationship between genetic susceptibility loci, NIPs, and neurocognitive impairment. Towards this end we will use Network Edge Orienting to determine the causative relationship between genotype and NIPs. This will be integrated with structural equation modeling, thus allowing creation of a comprehensive pathway model of HAND that includes genotype, NIPs, neurocognitive functioning, and important co-factors. PUBLIC HEALTH RELEVANCE: The impact of HIV-associated neurocognitive disorders (HAND) is substantial, affecting upwards of 50% of HIV-infected individuals; therefore, elucidating the neuropathogenesis of this disorder and identifying pharmaceutical targets will improve quality of life for tens of thousands within th United States alone. In recent years, a small number of genetic susceptibility loci have been identified that increase risk for HAND, suggesting that perturbation of the physiological pathways their gene products are involved in modifies HAND pathogenesis; however, nothing is known of what pathophysiological changes these genetic variants cause. Delineating this relationship will help to clarify the molecular and physiological pathways involved in HAND neuropathogenesis, and this will lead to identification of potential pharmaceutical targets.